Renin is a natural enzyme which is released into the blood from the kidney. It cleaves its natural substrate, angiotensinogen, releasing a decapeptide, angiotensin I. This is in turn cleaved by converting enzyme in the lung, kidney and other tissues to an octapeptide, angiotensin II. Angiotensin II raises blood pressure both directly by causing arteriolar constriction and indirectly by stimulating release of the sodium-retaining hormone aldosterone from the adrenal gland causing a rise in extracellular fluid volume. Inhibitors of renins have been sought as an agent for control of hypertension and hyperaldosteronism.
The present invention concerns novel peptides which inhibit renin. The present invention is also concerned with pharmaceutical compositions containing the novel peptides, methods of treating renin-associated hypertension and of treating hyperaldosteronism, and methods for preparing the novel peptides.
U.S. Pat. No. 4,479,941 covers certain renin-inhibitory peptides of the formula ##STR1## wherein: A is hydrogen; ##STR2## where n is 0 to 5 and R.sup.3 has the same meaning as set out further below, and may additionally be hydrogen;
B is absent; glycyl; sarcosyl; or ##STR3## D is absent; or ##STR4## where Z is (CH.sub.2).sub.n and n is 1 or 2; or --S--; R.sup.1 is hydrogen; C.sub.1-4 alkyl, hydroxy C.sub.1-4 alkyl; phenyl, phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; indolyl; 4-imidazolyl; amine C.sub.2-4 alkyl; guanidyl C.sub.2-3 alkyl; or methylthiomethyl; PA1 R.sup.2 is hydrogen C.sub.1-4 ; alkyl; phenyl; phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; or indolyl; PA1 R.sup.3 is C.sub.3-6 alkyl; C.sub.3-7 cycloalkyl; phenyl; or C.sub.3-7 cycloalkyl or phenyl mono-substituted with a member selected from the group consisting of methyl, trifluoromethyl, hydroxy, methoxy, fluoro, chloro, bromo, and iodo; PA1 R.sup.4 is hydrogen; or ##STR5## where R.sup.5 is hydrogen; C.sub.1-14 alkyl; hydroxy; or C.sub.3-7 cycloalkyl; and PA1 E is EQU --Y--(CH.sub.2).sub.n --R.sub.6 ( 1) PA1 where PA1 Y is --NH-- or --O--; PA1 n is 0 to 5; and PA1 R.sup.6 is hydrogen; hydroxy; C.sub.1-4 alkyl; PA1 C.sub.3-7 cycloalkyl; aryl; aryl substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, trifluoromethyl, hydroxy, C.sub.1-4 alkoxy, amino, mono- or di-C.sub.1-4 alkylamino, and halo; amino; mono-, di-, or tri-C.sub.1-4 alkylamino; guanidyl; heterocyclic; or heterocyclic substituted with up to five members independently selected from the group consisting of C.sub.1-6 alkyl, hydroxy, trifluoromethyl; C.sub.1-4 alkoxy, halo, aryl, aryl C.sub.1-4 alkylamino; ##STR6## where Y is as defined above; PA1 n is 0 or 1; PA1 k is 0 or 1; PA1 l is 1 to 4; PA1 m is 1 to 4; and PA1 R.sup.6 and R.sub..alpha..sup.6 may be the same or different and have the same meaning as R.sup.6 above and R.sub..alpha..sup.6 may additionally be ##STR7## where R.sup.7 is hydrogen or C.sub.1-3 alkyl; or ##STR8## where Y is as defined above; PA1 n is 0 or 1; and PA1 Z is ##STR9## where n is 0 or 1; and PA1 R.sup.7 is as defined above; or ##STR10## where n is 0 or 1; wherein all of the asymmetric carbon atoms have an S configuration, except for those in the B, D, and E substituents, which may have an S or R configuration; and a pharmaceutically acceptable salt thereof. PA1 X=H or N-protecting gp.; PA1 D=absent or aromatic or lipophilic aminoacyl both opt. reduced at CO; PA1 E=absent or aromatic aminoacyl or basic aminoacyl, both opt. N(.alpha.)-alkylated and/or reduced at CO; PA1 A=a gp. of formula (III) or (IV): ##STR11## R.sub.4 -R.sub.6 =H, alkyl, (CH.sub.2).sub.n OH or (CH.sub.2).sub.n NH.sub.2 ; PA1 n=2, 3 or 4; PA1 G.sub.1 and G.sub.2 =(CH.sub.2)--(CH.sub.2).sub.m, (CH.sub.2).sub.m CO or CO(CH.sub.2).sub.m ; PA1 m=0-3; PA1 R.sub.1 and R.sub.2 =alkyl, arylmethyl, lipophilic gp. or H; PA1 M=(i) CH(OH)(CH.sub.2).sub.m', (ii) CH(NH.sub.2)(CH.sub.2).sub.m', (iii) CH.sub.2 (CH.sub.2).sub.m', (iv) CO(CH.sub.2).sub.m', (v) (CH.sub.2).sub.m' NX or (vi) CH(NH.sub.2)(CH.sub.2).sub.m' CONH; PA1 m'=0-2; PA1 provided that (i) when M is (i), (iii) or (iv) and m'=1, then 2-4 of D, E, B and Z are present; and when M is (v) and m'=1, then 3 or 4 of D, E, B and Z are present; and PA1 (2) when M is (i), (ii) or (iv), then R.sub.5 and R.sub.6 are H, and when M is (iii) or (v), then if one of R.sub.4 -R.sub.7 is (CH.sub.2).sub.n OH or (CH.sub.2).sub.n NH.sub.2, the others are H or alkyl; PA1 Y.sub.1 =CO, CH.sub.2, CH(OH), CH(NH.sub.2) or CH.sub.2 NR.sub.3 ; PA1 B=absent or lipophilic or aromatic aminoacyl both opt. N(.alpha.)-alkylated and/or reduced at CO; PA1 Z=absent or aromatic aminoacyl or lipophilic aminoacyl both opt. N(.alpha.)-alkylated and/or reduced at CO; PA1 W=OH or other terminal gp., OR.sub.3, NH.sub.2, NHR.sub.3, N(R.sub.3).sub.2 or a N-heterocyclic 5- or 6-membered ring contg. 1-3N, O or S and opt. unsatd. and opt. substd. by R.sub.3 or R.sub.3 CH.sub.2 ; PA1 or Z--W=gp. of formula (V): ##STR12## L=NH, O or NR.sub.3 ; Q=H, 1-4C alkyl, aryl, imidazol-4-yl or indol-3-yl. PA1 n is 0 or 1, and the compound must contain at least 1 link where n is 1, PA1 acyl is BOC, NVA, Z, IVA, IBU, benzoyl, ##STR20## X is PHE, TRP, CYCLOHEXYLALA, NAPHTHYLALA, HOMOPHE, (Me.sup.5)-PHE, VAL, ILE, or LEU; PA1 Y is absent, PHE, HIS, HIS(BOM), GLY, PHGLY, LEU, VAL, ILE, ORN, ORN(PHT), ARG, or ARG(NO.sub.2); PA1 T is STA, PHSTA, CYSTA, LEU, CYCLOHEXYLALA or PHE; PA1 W is absent, LEU, GLY, or ILE; PA1 V is absent, LEU, or ILE; PA1 U is ##STR21## A is ##STR22## B is --CH.sub.2 NH--; C is ##STR23## D is --CH.sub.2 NH--; and E is --CH.sub.2 NH--, --CH.sub.2 NHZ. PA1 n is 0 or 1, and the compound must contain at least 1 link where n is 1, PA1 acyl is BOC, NVA, Z, IVA, IBU, benzoyl, ##STR25## X is PHE, TRP, CYCLOHEXYLALA, NAPHTHYLALA, HOMOPHE, (Me.sup.5)-PHE, VAL, ILE, or LEU; PA1 Y is absent, PHE, HIS, HIS(BOM), GLY, PHGLY, LEU, VAL, ILE, ORN, ORN(PHT), ARG, or ARG(NO.sub.2); PA1 T is STA, PHSTA, CYSTA, LEU, or CYCLOHEXYLALA; PA1 W is absent, LEU, GLY, or ILE; PA1 V is absent, LEU, or ILE; PA1 U is ##STR26## A is ##STR27## B is --CH.sub.2 NH--; and E is --CH.sub.2 NH--, --CH.sub.2 NZ.
PCT application No. 84/00032 relates to certain renin inhibiting peptides of the formula EQU X-D-E-A-B-Z-W
wherein